Dr. Simen is a clinical psychiatrist with a Ph.D. degree in Neurobiology. His career goals are to become an independent investigator in the Aging field, with a focus on how genomic changes that occur with age influence risk for cognitive and behavioral disorders. The career development proposal is directed at providing him with the necessary training to become a leader in the field, including training in epidemiology and other clinical aspects of aging, synaptic ultrastructure, cognition in rodents, behavioral neuroscience, proteomics methods, epigenetics, management and leadership skills, and networking with the aging research community. The mentorship team includes world-class experts in their respective disciplines and has developed a list of performance criteria that will be used to gauge progress. Yale University provides an excellent environment for this work, including world-class lab space, equipment, technical expertise, mentorship, and other resources to ensure that the career development and research activities in this proposal are successfully completed. The research proposal is directed at the fact that depression, anxiety, and cognitive decline in cause significant disability in the elderly. Aging and stress have similar effects on dendritic architecture and these structural changes contribute to vulnerability for depression, anxiety, and cognitive decline with aging. We hypothesize that aging is associated with epigenetic changes that increase dendritic vulnerability to the effects of stress and other insults. This proposal seeks to characterize the genomic changes associated with aging in the prefrontal cortex and how they interact with stress to determine risk for dendritic and behavioral pathology. We believe that the results of this work will have relevance to understanding how aging affects risk for neuropsychiatric disease in response to a wide variety of homeostatic challenges. Relevance: Depression, anxiety, and cognitive decline in the elderly are a serious public health concern because they detract from quality of life and lead to significant disability. Understanding how aging leads to increased risk for these conditions, particularly during periods of stress, is therefore of great importance and is the focus of this work.